Molecular Mechanisms of Sepsis

Molecular Mechanisms of Sepsis Title: Protein-protein interaction network and functional module analysis to reveal the mechanism of sepsis in polytrauma patients Highlights: We explored the molecular basis of sepsis induced by polytrauma using PPI network. A total of 342 DEGs including 110 up- and 232 down-regulated genes were obtained. TRAF3 was related with the innate immune responses in sepsis. ITGB3 was the key gene involved in coagulation dysregulation in sepsis. CASP6 and RASA1 played key roles in the cell apoptosis mechanism of sepsis. Abstract Objective Sepsis represents the systemic inflammatory response to microbial infection. The pathogenesis of sepsis remains unclear. In this study, we aimed to explore the molecular mechanism of sepsis inpolytrauma patients. Methods The differentially expressed genes (DEGs) between the polytrauma patients with and without sepsis were identified by analyzing the GSE12624 microarray data using the limma package of R. The protein-protein interaction (PPI) network was extracted from the human PPI datasets by using MATLAB. The functional modules in the PPI network were identified by the MCODE network clustering algorithm. The KEGG pathway analysis was performed in each module. The phylogenetic tree was constructed using phylogeny inference package (PHYLIP). Result Total of 342 DEGs including 110 up- and 232 down-regulated genes were obtained. The PPI network identified several hub genes which had more interactions with others, such as TRAF3, ITGB3, CASP6 and RASA1. Further phylogenetic analysis indicated the high conservation of these hub genes. In the module analysis, four significant modules were identified. All the genes (COL1A2, FN1, ITGA2B, ITGB3 and CD36) in module 2 were enriched in extracellular matrix (ECM)-receptor interaction pathway. In module 4, CASP6 and CASP3 were enriched in apoptosis pathway. Conclusion We predicted genes such as TRAF3, ITGB3, CASP6 and RASA1 which were closely associated with sepsis induced by polytrauma. Among them, ITGB3 may play key role in the coagulation dysregulation of polytrauma patients with sepsis, and CASP6 and RASA1 may be the key genes in the cell apoptosis mechanism of sepsis. Keywords Sepsis, DEGs, GO, PPI network, phylogenetic tree Introduction Polytrauma is a syndrome of multiple injuries exceeding a defined severity with sequential systemic reactions that can lead to dysfunction or failure of remote organs and vital systems, which have not themselves been directly injured [1]. Sepsis, as one of the complications of polytrauma [2], is the systemic inflammatory response to microbial infection that often leads to increasing susceptibility to secondary infections, multiorgan failure, and death [3]. A sixteen years clinical study indicated that 10.2% of polytrauma patients infected sepsis during their hospital course [4]. Polytrauma is a major cause of morbidity and mortality in global and sepsis (3.1-17%) is one of the predominant causes of late death in polytrauma patients [5]. The disease severity is increasing according to the order of sepsis, severe sepsis and septic shock in the systemic inflammatory response syndrome (SIRS) [6]. Mortality has been reported to be as high as 45.6% for patients with severe sepsis or septic shock [7]. Based on the pathogenesis of sepsis, many therapies have been applied in the clinical practice such as antimicrobial therapy [8, 9] and hemodynamic support and adjunctive therapy [10, 11]. Currently, the Surviving Sepsis Campaign (SSC) has attempted to increase the awareness and establish the practice guidelines to improve the recognition and treatment for the patients with sepsis [12, 13]. At present, there are four approved mechanisms in the pathogenesis of sepsis [14]. The first one is dysregulated coagulation. Sepsis patients frequently manifest disseminated intravascular coagulation (DIC) with consumption of platelets and prolongation of clotting times [15]. The second one is inflammatory response. The inflammatory response is an important and central component of sepsis because the elements of response drive the physiological alterations that manifest as the SIRS [16]. Third, many cellular aspects become dysfunctional in sepsis which behave either excessive activation or depressed function [17]. The last one is metabolic alterations. It was reported that endogenous glucose production was markedly increased in the patients [18]. However, the specific molecular mechanisms of them remain entirely unclear. In this study, the differentially expressed genes (DEGs) between the polytrauma patients with sepsis and without sepsis were identified. Gene ontology (GO) analysis , protein-protein interaction (PPI) network and phylogenetic tree construction were performed to explore the molecular basis of sepsis induced by polytrauma. Materials and methods Microarray data The gene expression profile of GSE12624 based on the CodeLink UniSet Human I Bioarray platform (GE Healthcare/Amersham Biosciences) was downloaded from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). The dataset available in this analysis contained 70 samples including 34 polytrauma patients with sepsis and 36 polytrauma patients without sepsis. Data preprocessing and DEGs screening For the microarray data, Robust Multichip Average (RMA) in the Affy package of R was used to compute normalized expression measures from the raw expression values. Probe annotation was obtained by using the Bioconductor package. The limma package was used to identify the DEGs with p-value 1 [19]. GO enrichment analysis of DEGs GO analysis was performed using the DAVID online tool (http://david.abcc.ncifcrf.gov/) [20]. For GO enrichment of DEGs, we selected GOTERM_BP_FAT, GOTERM_CC_FAT and GOTERM_MF_FAT as the gene set categories. A p-value of less than 0.05 was set as the cut-off criterion. PPI network construction The human PPI datasets with 108477 interacting protein pairs were downloaded from PINA2 (http://cbg.garvan.unsw.edu.au/pina/interactome.stat.do) at December 26, 2013. The PPI networks of the DEGs in sepsis were extracted from the human PPI datasets by usingMATLAB [21]. The proteins in the network served as nodes and the degree of a node corresponded to the number of interactions with other proteins [22]. The protein with high degree was considered as the hub node. Identification of functional modules in PPI network PPI network visualization and network parameters evaluation were performed by using Cytoscape software. The modules were identified by the MCODE (a cytoscape plug-in) network clustering algorithm with the default parameters [23]. The module with score larger than 2 was considered as significant. KEGG pathway analysis of each module was performed by applying the DAVID annotation tool. Phylogenetic tree construction In this study, we constructed the phylogenetic tree based on the nucleotide sequences to investigate the sequence conservation of the DEGs whosedegree were large than 30. The BLAST program is used to search for homologous sequences of these DEGs. The DNA sequence of these DEGs and their homologous genes in FASTA format were obtained from the nucleic acid database in NCBI (http://www.ncbi.nlm.nih.gov/nuccore). The phylogenetic tree was constructed by using phylogeny inference package (PHYLIP) with the default parameters [24]. The gene conservation was estimated by the distance from gene to the phylogenetic tree root. Result DEGs between the patients with and without sepsis After statistical analysis of the microarray data, a total of 342 DEGs were screened out. Among them, 110 were down-regulated and 232 were up-regulated in sepsis. The top 20 significantly up- and down-regulated DEGs are shown in Table 1. GO enrichment analysis The 342 DEGs were significantly enriched into 95GOterms including 81 biological processes terms, 10 cellular component terms and 4 molecular function terms. The top 10 GO biological processes termswere mainly related to the purine base (purine base biosynthetic process, purine base metabolic process, purine nucleoside monophosphate biosynthetic process and purine ribonucleoside monophosphate biosynthetic process), nucleobase (nucleobase metabolic process and nucleobase biosynthetic process) and regulation of protein modification (regulation of protein modification process and positive regulation of protein modification process). The 10 significantly enriched GO terms of cellular component included four lumen related terms (organelle lumen, membrane-enclosed lumen, intracellular organelle lumen and nuclear lumen), two membrane related terms (extrinsic to membrane and plasma membrane part) and four other cellular component terms (peroxisome, microbody, nuclear body and Golgi apparatus) . For molecular function, four significant GO terms were enriched finally. They were acyl-CoA binding, sons of mothers against decapentaplegic homologue (SMAD) binding, aryl hydrocarbon receptor binding and potassium channel inhibitor activity (Table 2). PPI network of DEGs A PPI network consisting of 225 DEGs and 1048 non-DEGs is shown in Fig. 1. This network included 1145 gene nodes and 1273 interactions. The connectivity degree of each node in this PPI network was calculated and the results of top 20 nodes are listed in Table 3. Among them, the genes CRK (encoding CDC2 related protein kina), RASA1 (encoding RAS p21 protein activator 1), TRAF3 (encoding tumour-necrosis-factor receptor associated factor 3), ZHX1 (encode zinc-fingers and homeoboxes), ITGB3 (encoding integrin ÃŽ ²3), RPA1 (encoding replication protein A1), JAK3 (encoding Janus kinases 3), and CASP6 (encoding caspase-6) with the degree over 30 were selected as the hub genes. Module analysis of PPI network A total of 7 modules were constructed by using MCODE plug-in. After excluding the modules with the score less than 2, 4 significant modules were considered as functional ones associated with sepsis (Table 4). According to the Fig. 2, the numbers of nodes and edges were similar in each model. The detailed results of KEGG pathway analysis for each module are provided in Table 5. For module 1, no pathway was enriched in the KEGG pathway analysis. For module 2, a total of 14 significant enriched pathways were identified. Among them, all the genes in this module were enriched in the pathway of extracellular matrix (ECM)-receptor interaction. In addition, except CD36 (encoding glycoprotein IV), the other four genes (ITGB3 and ITGA2B encoding integrin ÃŽ ±IIbÃŽ ²3, COL1A2 encoding the ÃŽ ± 2 chain of type 1 collagen and FN1 encoding fibrinogen 1) were enriched in the focal adhesion and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. There were three significant enriched pathways in module 3. HIF1A (encoding hypoxia inducible factor-1), ARNT (encoding arylhydrocarbon receptor nuclear translocator) and ARNT2 (encoding arylhydrocarbon receptor nuclear translocator 2) were enriched in the pathway of renal cell carcinoma and pathways in cancer. HIF1A and ARNT were enriched in the pathway of Hypoxia-inducible factor 1 (HIF-1) signaling. For the module 4, five significant pathways were found. Among them, CASP3 (encoding caspase 3) and BIRC5 (encoding baculoviral IAP repeat–containing 5 and also called survivin) were enriched in the pathway of colorectal cancer, hepatitis B and pathways in cancer. CASP6 and CASP3 were enriched in apoptosis pathway. CASP3 and RASA1 were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway (Table 5). Phylogenetic tree analysis Based on the result of PPI network analysis, the selected hub genes were chosen to construct the phylogenetic tree. The phylogenetic tree of ZHX1 was unable to be constructed, as only three homologous sequences were searched out. The phylogenetic trees of the other seven hub genes were constructed by the DEGs and their top nine significant homologous genes. The results showed that CRK, RASA1, TRAF3, ITGB3, RPA1 and CASP6 were the genes that were closer to tree roots indicating that the conservation of these genes was high during evolution. However, the conservation of JAK3 was low because of appearing in the late period of evolution (Fig. 3). Discussion Currently, sepsis remains a serious clinical problem. The four approved mechanisms of sepsis were dysregulated coagulation, inflammatory response, and cellular dysfunctional and metabolic alterations. However, the specific molecular mechanisms are still incompletely understood. For better understanding the pathogenesis, we identified and analyzed the DEGs between the patients with and without sepsis. As a result, a total of 342 DEGs including 110 up-regulated genes and 232 down-regulated genes were found. These genes were significantly enriched in GO terms including purine base biosynthetic process, regulation of protein modification process and peroxisome. Among them, the process of purine base biosynthesis is the most significantly enriched process. It was reported that de novo purine biosynthesis was essential for infectivity, growth and virulence of many bacteria in mammals [25]. The pathogenesis of sepsis was related with the bacterial infection [26]. Therefore, the purine base biosynthesis process may associate with sepsis based on the tissue response to bacterial infection. For the regulation of protein modification, Wu et al. reported that the alterations in the phosphorylation of myofibrillar proteins and the Ca2+ sensitivity of myofibrillar ATPase might contribute to alter cardiac function during the progression of sepsis [27]. The cardiac dysfunction was the clinical characteristic in severe sepsis and septic shock [28]. Thus, the phosphorylation of myofibrillar proteins may be related with the sepsis-induced cardiac dysfunction. Furthermore, we mapped the DEGs to the PPI network and identified high conserved hub genes. Among them, the high conservation of CRK, RASA1, TRAF3, ITGB3, RPA1 and CASP6 were proved by the phylogenetic tree analysis. They may be the crucial genes in the pathogenesis of sepsis. For TRAF3, it is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family [29]. This protein participates in the activation of the innate immune response [30]. In the PPI network, TBK1 (encoding TANK-binding kinase 1) was a non-DEG interacted with TRAF3. It was reported that TIR domain-containing adaptor-inducing IFN-ÃŽ ² (TRIF) could interact with noncanonical IKKs (IKKà Ã‚ µ and TBK-1) and IKKÃŽ ¹ (also called IKKà Ã‚ µ) through TRAF3 in the Toll-like receptors (TLR) signaling pathway [31]. The innate immune system constitutes the first line of defense by rapidly detecting invading pathogens through the TLR [32] and is a danger signal in systemic inflammatory response syndrome and sepsi s [33]. Thus, TRAF3 may be the mediator of innate immune responses in sepsis induced by polytrauma. We also performed the modular analysis of the PPI network and four functional modules were identified. Based on the result of the KEGG pathway analysis of each module, we found that the pathways in module 2 and 4 were more related with sepsis. The ECM-receptor interaction pathway was the most significant pathway in module 2 and all the genes of this module were enriched in this pathway. Fibronectin and collagen are the components of ECM [34]. Integrin family are the receptors transducing signals from the ECM [35]. Among them, integrin ÃŽ ±IIbÃŽ ²3 is the platelet integrin promoting theaggregation of platelets [36-38]. Moreover, it was reported that collagen type I could induce the aggregation of platelet [39]. Integrin ÃŽ ±IIbÃŽ ²3 is one of the platelet collagen receptors in platelets [40]. It was reported that platelet-specific elements initiated at the cytoplasmic domains of integrin ÃŽ ±IIbÃŽ ²3, which was a signal that leaded to conformational changes within the extracellular do mains of integrin and expression of the fibrinogen receptor, then the simultaneous occupancy on adjacent platelets of receptors with dimeric fibrinogen molecules leaded to platelet aggregation [41]. In addition, CD36 is spatially associated with the ÃŽ ±IIbÃŽ ²3 integrin on the surface of platelets [42]. Thus, we speculated that the binding of collagen type I and ÃŽ ±IIbÃŽ ²3 might need the participation of CD36, and then conformational changes within the extracellular domains of integrin and the binding between fibrinogen and fibrinogen receptor could lead to platelet aggregation. Disseminated platelet aggregation is one of the characteristics of the DIC in sepsis [43, 44]. The up-regulated expression of ITGB3 in sepsis may lead to the disseminated platelet aggregation. Hence, we concluded that the coagulation dysregulation in the polytrauma patients with sepsis may be associated with the increase of disseminated platelet aggregation caused by the up-regulated expression of ITGB3. Thus, ITGB3 may play key roles in the coagulation dysregulation of the polytrauma patients with sepsis. Hub nodes CASP6 and RASA1 were predicted to be closely interacted with each other in module 4. Besides, CASP3, TOP1, BIRC5 and AURKB (Aurora B kinase) were also included in module 4. Among them, CASP6 and CASP3 were enriched in apoptosis pathway. It was reported that CASP6 may be associated with the cell apoptosis in sepsis [45] and blocking caspases might have some beneficial effects in decreasing cell apoptosis in sepsis [46]. Thus, we further confirmed that the up-regulated expression of CASP6 may promote cell apoptosis in sepsis. Besides, TOP1 is cleaved late during cell apoptosis by CASP6 and CASP3 [47]. The TOP1 cleavage complexes contribute to cell apoptosis [48]. Therefore, the increase of these complexes induced by the up-regulated CASP6 can promote the cell apoptosis in sepsis. Moreover, full-length TOP1 could induce DNA cleavage by single-strand breaks which is the signal of cell apoptosis [49, 50]. Therefore, the exaggerated gene expression of TOP1 in our study might cont ribute to cell apoptosis in sepsis. In addition, it was reported that CASP3 could modulate a given set of proteins to generate, depending on the intensity of the input signals, opposite outcomes (survival vs death) through differential processing of RASA1 [51]. Some articles reported that low CASP3 activity leaded to the cleavage of the RASA1 protein into an amino-terminal fragment [52, 53]. RASA1 bound BIRC5 is a bifunctional protein complex that can suppress cell apoptosis and regulated cell division, so as to generate anti-apoptotic signals [54]. AURKB exists in a complex with BIRC5 [55]. Considering the up-regulated expression of RASA1 and AURKB, we speculated that there may be a switch mechanism of CASP3-RASA1 in cell apoptosis and BIRC5 and AURKB might play roles in the anti-apoptosis mechanism of RASA1. In summary, CASP6 and RASA1 are the key genes in the pathogenesis of sepsis induced by polytrauma. Conclusion In this study, we obtained four key genes related with pathogenesis of sepsisinduced by polytrauma. Among them, TRAF3 was related with the innate immune responses in sepsis,ITGB3 may play key role in the coagulation dysregulation of the polytrauma patients with sepsis and CASP6 and RASA1 were associated with the mechanism of cell apoptosisin sepsis. For further investigating the association of these hub nodes with sepsis and verifying the role of the interactions among the genes in the pathogenesis of sepsis, more studies are required in the future.

Rhetorical Techniques in Richard Wright’s Black Boy Essay -- Wright Bl

Rhetorical Techniques in Richard Wright’s Black Boy Richard Wright uses language in his novel, Black Boy, as a source to convey his opinions and ideas. His novel both challenges and defends the claim that language can represent a person and become a peephole into their life and surroundings. Richard Wright uses several rhetorical techniques to convey his own ideas about the uses of language. First, Wright’s language and writing style in Black Boy challenge Baldwin’s ideas. For example, pages 18-19 are purely figures pf speech that convey the writer as being far different than Wright. â€Å"There was the languor I felt when I heard green leaves rustling with a rain like sound.† This quote was just one of the sensory enticing statements Wright used to show his delicate way of writing; a way of writing that would not typically belong a lower class black male in the 1940’s. In addition, the organization of the passage was unique in the sense of how each statement was separate, in order to make each important and each a work of art. Assuming Baldwin having read this passage, he would ...

Impact of christianity Essay

Christian dogmas have always been intertwined with philosophy regardless of the fact that most of the time both philosophers and theologians had polar opinions associated with religion and philosophy respectively. The first mentioning of philosophy in the Bible was encountered in the New Testament: See to it that no one makes a prey of you by philosophy and empty deceit, according to human tradition, according to the elemental spirits of the universe, and not according to Christ. (Colossians 2:8) Nevertheless, one of the earliest Christian representatives Tertullian always disagreed with the combination of ordinary temporal philosophical views and spiritual exalted religious dogmas. To the contrary, another religious thinker St. Augustine of Hippo defended the idea of inter-complementation of abstract science and Christian faith only in case of their mutual compatibility. St. Thomas Aquinas made great contribution to the Christianity’s impact on philosophy, as he was the first to distinguish these two important sectors of human perception of surrounding environment. He claimed that o Owing to philosophy information is being received through basic sensory functions: smell, touch, vision, hearing, and taste. Also, it is possible to prove and check the data according to laws of physics initially based on philosophy as well. o Owing to Christianity, information is not something to be proved or argued. It is to be accepted axiomatically especially when it is closely connected with God and Divine. After the Middle Ages the double nature of Jesus Christ (divine and human) was put in doubt and required explicit evidence regarding the origin and function of God. Philosophy could not succeed in answering this question, as the notions of humanity and divinity do not logically coincide with each other. Therefore, certain attempts were made with the help of Christianity to resolve the issue of imbalance. Thus, we need to mention three major reasons why philosophy was isolated from Christianity. ? First of all, philosophers from English-speaking world were predominantly atheists and rejected all spiritual and divine aspects of human activity. They required strong logical evidence and proof for subjects of their investigation and discussion ? Secondly, rejecting Christian dogmas philosophers were constantly seeking alternative ways to find proof for their arguments and new methods and evidences hidden in other religions.? Thirdly, philosophers believed that the language of religion and theology is too incoherent, irrational, and inconsistent that the meaning, no matter how important or of current importance it may be, loses its significance. Philosophical issues that have become Christianized include: ? Trinity: it was no clear for many thinkers why God consisted of three persons: God the Father, God the Son, and God the Holy Spirit. In the 7th century the Council of Toledo announced: â€Å"we may say God the Father, God the Son, and God the Holy Spirit; but they are not three Gods, he is one God†. Similar to how a solar system may consist of numerous cosmic bodies. ? Sacrifice and atonement: philosophers believed that one punishment is enough to give birth to another, which is not always fair. However, Christianity responded by proving that punishment has moral nature and it is not something that exceptionally deals with evil. In conclusion, we may add that Christianity had a great impact on philosophy since early times. References Moore, N. B. , & Bruder, K. (2004). Philosophy: The Power of Ideas. 6th edition. New York: McGraw-Hill Humanities.

Criminal Justice Act 2003 - Free Essay Example

Sample details Pages: 10 Words: 2892 Downloads: 1 Date added: 2017/06/26 Category Law Essay Type Essay any type Level High school Did you like this example? Criminal Justice Act 2003 ‘Parliaments purpose in the legislation, as we divine it from the terms of the Act, was to assist in the evidence based conviction of the guilty, without putting those who are not guilty at risk of conviction by prejudice (R v Hanson [2005] 2 Cr App R 21, Rose LJ at [4]). In light of the above statement, evaluate the provisions of the Criminal Justice Act 2003, and the relevant case law under the Act, relating to attack on anothers character. Sections 98 to 113 of the Criminal Justice Act 2003 (CJA) represent a significant change from the accepted common law approach to the methods by which bad character evidence could be introduced in the course of criminal trial proceedings. Don’t waste time! Our writers will create an original "Criminal Justice Act 2003" essay for you Create order Notwithstanding the criticisms directed against the legislation from various quarters, an objective appraisal of the provisions themselves and the judicial interpretations provided since the passage of the CJA confirms that to a large degree, the observations of Rose LJ noted in the title as to Parliaments purpose are accurate. As importantly, the evidentiary regime established in the CJA strikes a fair and fundamental balance between the principles of reasonable doubt, the right of the defendant to make full answer and defence to a criminal charge, and the societal interest in the effective prosecution of crime. This paper commences with an overview of the most important changes to the previous law concerning bad character that are now established by the CJA. The procedure contemplated by the joint effect of the CJA provisions and the Criminal Procedure Rules (CPR) is also considered and evaluated. The paper then provides an examination of the principles that support the ad missibility of bad character evidence concerning defendant and non-defendant witnesses, with the seven specific ‘gateways for such evidence as defined by the CJA given specific consideration. The cases decided since 2004 and relevant academic commentaries are also highlighted. There are three particular aspects to the CJA regime that guide the present analysis and require specific attention in this regard. These are: The abolition of the common law rules that previously governed such admissibility as well as the prior rules provided in the Criminal Evidence Act 1898 concerning the cross-examination of defendants as to character Evidence of bad character concerning a non-defendant is admissible by leave of the court on specific grounds Evidence of the defendants bad character is generally admissible on a wider range of prospective trial issues, by virtue of the seven specific ‘gateways established by the CJA There is no question that the Criminal Justice Act 2003, Part 11 represents a fundamental alteration of prior English law concerning the general admissibility of bad character evidence. Placed in an admittedly restricted nutshell, the prior law confirmed that the prosecution could not adduce evidence of the defendants bad character (other than evidence concerning the offence charged or offences against the administration of justice committed in relation to the offence charged). The prosecution was also prohibited from leading evidence of the defendants propensity to commit criminal acts even if relevant to the charge. In this way, the previous bad character evidence rules were an exception to the general rule that all relevant evidence is admissible in a criminal trial. The traditional caveat advanced in this respect that justified the exclusion of evidence of bad character was that it is often irrelevant to the proof of a defendants guilt; insofar as it is relevant, its prej udicial effect outweighs its probative value. The reworking of the law in the CJA commences with the definition of bad character provided at s.98 and s.112. There are two specific ingredients in the definition. Bad character evidence may include any evidence of misconduct or a â€Å"disposition† towards misconduct; it may also include misconduct established through evidence of the â€Å"†¦commission of an offence or other reprehensible conduct†. Subject to special procedures that governed the admissibility of ‘similar fact evidence that also may have provided the basis for bad character evidence to be admitted against a defendant, the case law that has subsequently interpreted the admittedly broad expressions ‘misconduct and ‘reprehensible conduct as employed in the CJA has given each phrase a sensible meaning. If the entire purpose of criminal evidence rules may be summarised as achieving the balance between private rights to full def ence and the interest of the state as contended in the papers opening paragraph, the case law achieves this purpose. In Weir, the Court of Appeal determined that the propensity to commit crime on the part of an accused could be proven with reference to the defendants commission of other crimes, but the prosecution could establish propensity by other means. The ‘other means were fleshed out in the other case law, including Renda, where the Court ruled that a prosecution witness may be cross-examined about incidents of misconduct known to the defendant which had never themselves been the subject of a criminal charge. It is contended that a greater breadth afforded judicial discretion to admit bad character does not improperly impair the defence so much as it ensures a greater range of relevant evidence may be considered by the court. This discretion is placed within a procedural construct that has proven useful in the relatively brief life of the CJA provisions. The pr osecution is required to provide the defendant a minimum of 14 days notice of its intention to introduce bad character evidence at trial; the defendant has the opportunity to object prior to the tendering of the proposed evidence and a ruling will be obtained accordingly. The procedure applies to bad character evidence proposed by the prosecution and such evidence a defendant proposes to call with respect to a co-defendant. These rules achieve two important results not necessarily guaranteed under the former regime where applications of this nature were regularly permitted to be made by trail judges within the trial proper. The defence will not be surprised or in any way caught unawares by the prosecution application to rely on bad character evidence. In a system of justice that historically exhibited reluctance to provide full disclosure of the entire case relied upon by the prosecution in advance of trial, this Rule is a very positive development that promotes the overarc hing principle of procedural fairness. The secondary benefit achieved through this procedure is a more focused trial. Jurors and witnesses ought to expect that they shall attend a proceeding that will not be diverted from the orderly calling of evidence by virtue of unexpected motions brought to resolve questions of admissibility that can be resolved efficiently at the pre-trial application stage. Further, the notice provisions provided in the CJA and the Rules of Criminal Procedure permit all parties to make appropriate enquiries in advance of trial concerning the intended evidence. In this important sense, the relevance of the evidence can be buttressed or challenged in a thorough and effective way where appropriate. The distinction in the treatment of bad character evidence that pertains to non-defendants and defendants is confirmed in s. 100 CJA. It is important to note that the often problematic evidentiary rules concerning the cross-examination of a sexual assault complainant are excluded from the operation of the CJA in this respect. It is contended that this exception is the one significant difficulty revealed by the revisions. The special provisions that were enacted to govern the admissibility of prior sexual history evidence have attracted significant attention. For example, there is a legitimate need to ensure that a defendant in a sexual offence prosecution is not permitted to equate the fact that a woman did not make complaint concerning his conduct at an earlier time with the conclusion that the present complaint must be false. Criminal trials should not be determined on the basis of ‘rape myths or stereotypical notions of how a rape victim ought to behave. However, it would be preferable that all criminal evidence be evaluated using the same criteria. The CJA framework is entirely suited to prevent the introduction of such evidence when the ‘gateway principles are applied; special consideration for specific offenc es undermines the cohesiveness of the law. In all other respects, the language used in s. 100 section provides the clearest possible demarcation between the permitted approaches to the tendering of non-defendant bad character evidence. Only where the proposed evidence is important explanatory evidence, or where the evidence is directed to an issue in the proceedings and it is of substantial importance to the presentation of the case as a whole may it be admitted. The section provides amplification on the definition of the phrase ‘important explanatory evidence as evidence without which the jury would find the case difficult or impossible to understand (all emphasis added). A semantic criticism may be made that the use of ‘difficult and ‘impossible in the same definitional expression is clumsy and may lead to inconsistency given the different each term provides as a condition precedent to admissibility. However, the underlying philosophy inherent in the s ection is sound. Bad character evidence that relates to non-defendants ought to be pre-screened by the trial judge to ensure its relevance and to give greater assurance that the trial process is not distracted from the consideration of important evidence. The subsequent case law has properly limited ‘misconduct evidence to exclude an arrest on a criminal charge; the section imposes a higher test with respect to the introduction of a non-defendants bad character than does the test for the introduction of a defendants bad character. Prospective bad character evidence concerning a defendant is potentially admissible through one or more of the seven procedural ‘gateways established in s. 101 (1) CJA. Each provision has a valid trial fairness objective; for example, bad character admitted on consent, or such evidence led to rebut a defence attack on another persons character are as rooted in common sense as they are fair adjudicative principles. The gateways that res tate the importance of explanatory evidence to give a fact situation appropriate context, and the traditional relevance / probative value versus prejudicial test developed in the common law warrant further examination in this regard. These are the most important and the most litigated provisions in the gateway structure. Edwards provides a useful example of how a court will assess how important background evidence must be to the understanding of the entire case. In this decision, the Court of Appeal confirmed that for a jury to properly understand the nuance of a heroin trafficking transaction, evidence could be called by the prosecution to explain how such transactions proceeded if they were to understand why a witness said that they could identify the defendant. Relevance to an important matter between the defence and the prosecution as described in s. 101 (1) (d) CJA is not restricted to the defendants alleged propensity to commit the subject crime or crime generally. The provision represents a barrier to the prosecution to call such evidence if it is not central to its chief purpose. For example, whilst the previous common law based limitations on the tendering of a defendants criminal record was often regarded as highly prejudicial to the prosecution, the revisions enacted in the CJA provisions do not countenance the wholesale introduction of such evidence, notwithstanding how attractive the evidence might be to the prosecution in the context of its desire to make the most of its position. Campbell is a decision that underscores why the CJA provisions strike the appropriate balance between defendant interests and the jurys ability to fairly decide the case. The trial judge in Campbell permitted the jury to hear evidence of the defendants two prior convictions without permitting them to hear any other background into those earlier events. It is not surprising that after the judges charge to the jury, this question was asked by the jur y, â€Å"What was the significance of revealing the defendants two previous assault convictions? Anything else we should know?The introduction of a criminal conviction alone absent information that provides context to the events that led to the previous entry may result in a skewed understanding of the defendant that prejudices the defence position; the approved course by virtue of Campbell is that the jury should be warned not to attach too much weight to bad character evidence, let alone conclude that the defendant is guilty simply because of his bad character. The substantial probative value requirement for bad character evidence as confirmed in s. 101 (1) (e) reinforces the traditional bedrock proposition of criminal evidence admissibility – judges must ensure that the probative value exceeds its prejudicial effect. By placing this important principle within the seven avenue evidentiary gateway, the CJA achieves a comprehensive effect concerning the admissibility and appropriate evaluation of bad character evidence that the prior pastiche of common law principles and circumstance driven exceptions could never achieve. When all of the provisions discussed above are taken together, a clear picture is drawn of the over all effect of the CJA with respect to the admissibility of bad character evidence. The law has been made more certain, but not at the expense of trial or procedural fairness. Relevance and probative value are given their due, and the ability of the defence to counter evidence that passes the CJA standards is unimpaired by its approach as contained in sections 98 to 113. Bibliography Statutes and Rules considered Canadian Charter of Rights and Freedoms 1982 Canada Evidence Act 1990 Criminal Justice Act 2003, ss. 98 -113 Criminal Procedure Rules, Part 35 Cases and reports considered A, R v [2001] 3 All ER 1 Boardman v DPP [1975] AC 421 Bovell and Dowds, R v [2005] EWCA Crim 1091 Campbell, R v [2007] 1 WLR 2798 Corbett , R. v. (1988) 41 C.C.C. (3d) 385 Edwards, Fysh Duggan Chohan, R v [2005] EWCA Crim 1813 Hanson, Gilmore and Pickstone, R v [2005] EWCA Crim 824 Highton, Van Nguyen and Carp, R v [2005] EWCA Crim 1985 Humphris, R v [2005] EWCA Crim 2030 Maxwell v DPP [1935] AC 309 OBrien v Chief Constable of South Wales Police [2005] 2 WLR 1038 Renda Others, R v [2005] EWCA Crim 2826 Weir Others, R v [2005] EWCA Crim 2866 Authorities considered Allen, Christopher (2006) Evidence QA 2005-2006 6/e London: Cavendish Routledge Crown Prosecution Service (2008). Bad Character Evidence [online] Retrieved March 15, 2010 at: https://www.cps.gov.uk/legal/a_to_c/bad_character_evidence/ Durston, Gregory (2004) ‘Bad character evidence and non-party witnesses under the Criminal Justice Act 2003 International Journal of Evidence and Proof 8, 4: 233-239 Law Commission Evidence of Bad Character in Criminal Proceedings (Report) [2001] EWLC 273(2) Fowles, Tony (2006) ‘Counterblast: The Criminal Justice Act 2003 The End of an Era? Howard Journal of Criminal Justice 45, 1: 71-73 OBrian, William E. (2009) ‘The Right of Confrontation: US and European Perspectives Warwick S chool of Law Research (2005) 121 LQR 481-510 Spencer, J.R. (2006). Evidence of Bad Character. Oxford: Hart Publishing. E.g. Fowles, Tony (2006) ‘Counterblast: The Criminal Justice Act 2003 The End of an Era? Howard Journal of Criminal Justice 45, 1: 71-73; OBrian, William E. (2009) ‘The Right of Confrontation: US and European Perspectives Warwick School of Law Research (2005) 121 LQR 481-510 The Bibliography reveals a large number of decisions in this area that were rendered between 2005 and 2007, the time frame within which the first trial decisions that applied the new CJA procedures were considered by the Court of Appeal. S.99 (1) CJA S.100 S. 101(1); the ‘gateways are subsections (a) through (g) Ss.98 to 113, CJA E.g. Escaping lawful custody or resisting arrest Maxwell v DPP [1935] AC 309 ; Lord Hailsham described the contests between prosecution and defence over propensity evidence as having left a â€Å"pitted battlefield † ( DPP v Boardman [1975] AC 421, 445), a testament to the historical importance of this issue in English law that underscores the significance of the CJA provisions Law Commission Evidence of Bad Character in Criminal Proceedings (Report) [2001] EWLC 273(2) Ss. 98, 112 Similar fact evidence admissibility (so called) was subject to the common law rules confirmed in Boardman v DPP [1975] AC 421, where the fundamental evidentiary test of prejudicial effect versus probative value applicable to all types of evidence generally governed similar fact admissibility Weir Others, R v [2005] EWCA Crim 2866 Renda Others, R v [2005] EWCA Crim 2826 By virtue of the combined operation of ss. 111(2), CJA and Part 35, Rules of Criminal Procedure ibid Ibid; see Hanson, [2005] EWCA Crim 824, para 117 Other Anglo-American jurisdictions such as Canada opted to enshrine full disclosure and prosecutorial notice in bad character evidence applications in their laws so me years ago. See Canadian Charter of Rights and Freedoms, s.7, the Canada Evidence Act, s. 12 and the leading case of Corbett (1988), 41 C.C.C. (3d) 385 at 399-401 See Humphris [2005] EWCA Crim 2030; Edwards [2005] EWCA Crim 1813; Bovell and Dowds [2005] EWCA Crim 1091, all cases that reinforce the relationship between procedural fairness and the s.111(2) CJA provisions S. 41 Youth Justice and Criminal Evidence Act; see also Durston, Gregory (2004) ‘Bad character evidence and non-party witnesses under the Criminal Justice Act 2003 International Journal of Evidence and Proof 8, 4: 233-239 R v A [2001] 3 All ER 1 ibid Weir, para 73, 74 Ibid, 36; see also OBrien v Chief Constable of South Wales Police [2005] 2 WLR 1038 S.101 (1) (a) S.101 (g) S. 101 (c); the traditional rules concerning res gestae statements will form a part of this consideration Ss. 101 (d) and (e), respectively [2005] EWCA Crim 1813, para 70, 71 Ibid; an important weaknes s in the prior law is discussed in Crown Prosecution Service (2008). Bad Character Evidence [online] Retrieved March 15, 2010 at: https://www.cps.gov.uk/legal/a_to_c/bad_character_evidence/, at part 2 (Principle); the prior law did not define what constituted background See e.g. Highton, Van Nguyen and Carp [2005] EWCA Crim 1985; see also generally Spencer, J.R. (2006). Evidence of Bad Character, c.1, 2 See Campbell [2007] 1 WLR 2798 Ibid Ibid, para 14 Ibid, para 45 Boardman , supra; see also Allen, Christopher (2006) Evidence QA 2005-2006 6/e Spencer, 4.20, 4.29